What Has Published Research Reported About Sermorelin?

What is sermorelin?

Sermorelin is the name given to a synthetic peptide that matches the first 29 amino acids of human growth hormone-releasing hormone (GHRH) and ends in a C-terminal amide. The literature writes it as GHRH(1-29)-NH2, hGRF(1-29)NH2 or GRF(1-29), and the DrugCentral database describes it as GHRH(1-29)-amide under CAS number 86168-78-7 (source 9). DrugBank lists its molecular formula as C149H246N44O42S, with a molecular weight of about 3,358 daltons (source 10).

A 1999 review in BioDrugs by Prakash and Goa described sermorelin as “the shortest synthetic peptide with full biological activity of GHRH” (source 7). That single phrase summarizes the two lines of work this profile follows: the 1980s chemistry that showed 29 residues were enough, and the plasma studies that showed how quickly the fragment is broken down.

The same 29-residue fragment is the starting point for several later GHRH analogs, including CJC-1295, which the Steadfast Research Group blog has profiled separately in what published research has reported about CJC-1295. Sermorelin is the unmodified fragment; it carries none of the substitutions or chemical handles those analogs added. As with every compound profile here, this page covers the published literature only and is written for researchers reading that record.

Where does the 29-residue sequence come from?

GHRH was first isolated from tumors rather than from the hypothalamus. In 1982, Guillemin, Brazeau, Böhlen, Esch, Ling and Wehrenberg reported in Science a 44-residue peptide with growth hormone-releasing activity taken from a human pancreatic tumor that had caused acromegaly (source 1). A synthetic replicate showed full biological activity in vitro and in vivo, and the authors reported that the tumor peptide was identical in biological activity and similar in physicochemical properties to the still uncharacterized releasing factor in hypothalamic extracts (source 1).

The same year, Rivier, Spiess, Thorner and Vale reported in Nature the characterization of a growth hormone-releasing factor from a human pancreatic islet tumour (source 2). Because the two groups worked in parallel, the older literature uses several names for the same hormone: growth hormone-releasing factor (GRF), GRH and GHRH. The numbers in brackets, as in GRF(1-29), give the residue positions a fragment spans, and the suffix NH2 marks an amidated C-terminus.

How did researchers find that 29 residues were enough?

Within two years of the isolation papers, Ling, Baird, Wehrenberg, Ueno, Munegumi and Brazeau published a systematic truncation study in Biochemical and Biophysical Research Communications (source 3). They made C-terminally shortened versions of human GRF by solid-phase synthesis, with either an amide or a free acid at the new C-terminus, and tested each one for growth hormone release from rat anterior pituitary cells in monolayer culture.

The pattern they reported was not a simple steady decline. Potency fell gradually to about 23 percent of the native peptide as residues were removed down to hGRF(1-34)OH. Removing more residues did not lower it further: the (1-31), (1-30) and (1-29) amides each held at about 50 percent of native potency (source 3). Shorter fragments, down to hGRF(1-21)NH2, still produced a full maximal response but only at very low potency, and bioactivity disappeared completely at hGRF(1-19)NH2. The authors concluded that the minimal core with full intrinsic activity spanned residues 3 to 21 (source 3).

In that series, the 29-residue amide was the shortest fragment that kept about half of the parent potency (source 3). It is the sequence later developed as sermorelin (sources 7 and 9). The distinction between potency and intrinsic activity matters for reading this paper, so the key terms are defined below.

Potency

How much of a peptide is needed to produce a given response. A fragment at 50 percent potency needed roughly twice the amount of the native peptide for the same effect in the 1984 assay (source 3).

Intrinsic activity

The maximal response a peptide can produce at saturating amounts. The (1-21) to (1-23) fragments reached full intrinsic activity despite very low potency (source 3).

Dipeptidylpeptidase IV (DPP IV)

A plasma enzyme that removes two-residue units from the amino terminus of susceptible peptides. It was identified as the main enzyme degrading GHRH in plasma (source 5).

NDA and ANDA

A new drug application and an abbreviated new drug application, the two US regulatory filings named in the 2013 Geref notice (source 8).

Which receptor does the GHRH sequence act on?

The GHRH receptor was cloned a decade after the hormone itself. In 1992, Mayo reported in Molecular Endocrinology a novel cDNA isolated from rat pituitary mRNA by amplifying sequences that encode G protein-coupled receptors (source 6). The encoded receptor had seven potential membrane-spanning domains and was homologous to the receptors for secretin and vasoactive intestinal peptide. Its mRNA was expressed predominantly, if not exclusively, in the anterior pituitary (source 6).

Mayo also isolated the human homolog and expressed it in human kidney 293 cells. Membrane fractions from those cells bound human GHRH with high affinity and specificity, and GHRH stimulated intracellular cAMP production in the transfected cells (source 6). The receptor study used native GHRH; the 1999 review described sermorelin as specifically stimulating growth hormone secretion from the anterior pituitary (source 7).

How quickly is GHRH(1-29) broken down in plasma?

The short life of GHRH in blood was documented in two papers from Frohman's group in the Journal of Clinical Investigation. In the first, published in 1986, native GHRH(1-44)-NH2 incubated in human plasma showed a half-life of about 63 minutes when total immunoreactivity was measured by radioimmunoassay, but the intact peptide measured by HPLC disappeared faster, with a half-life of about 17 minutes (source 4). The product still reacted in the immunoassay but had less than one-thousandth of the parent peptide's biological activity, and a degradation product was also detected in plasma after intravenous administration of GHRH to volunteers (source 4). The authors proposed that a plasma dipeptidylaminopeptidase could limit the hormone's action on the pituitary.

The 1989 follow-up named the enzyme and, importantly for sermorelin, tested the 29-residue fragment directly (source 5). Native GHRH(1-44)-NH2 and GHRH(1-40)-OH, and the shortened fragments GHRH(1-32)-NH2 and GHRH(1-29)-NH2, were all rapidly cleaved between residues 2 and 3, while GHRH(2-32)-NH2 was not cleaved at that site. An aminopeptidase inhibitor did not affect formation of the GHRH(3-44)-NH2 product, which the authors read as a single dipeptidyl step. Diprotin A, a competitive DPP IV inhibitor, blocked the conversion, and a D-amino acid at either position 1 or position 2 also stopped hydrolysis, a pattern the authors described as characteristic of DPP IV (source 5).

The trypsin-like products formed independently of prior DPP IV cleavage, and trypsin inhibitors greatly reduced them (source 5). In plasma from a pig carrying a human GHRH transgene, the major immunoreactive peak eluted with GHRH(3-44)-NH2. The authors concluded that GHRH degradation in plasma occurred primarily through DPP IV and to a lesser extent through trypsin-like enzymes (source 5).

Those findings set the agenda for later analog design. The 2005 paper that introduced CJC-1295 built its molecule on hGRF(1-29) with four amino acid substitutions, including a D-alanine at position 2, and reported that its albumin conjugates were stable against DPP IV in vitro (source 11). Sermorelin keeps the native residue at position 2, so the 1989 cleavage data apply to it as tested.

What is sermorelin's regulatory history?

Sermorelin acetate was marketed in the United States under the name Geref by EMD Serono. According to a 2013 Food and Drug Administration notice in the Federal Register, an ampule presentation was first approved under NDA 19-863 on December 28, 1990, and vial presentations were first approved under NDA 20-443 on September 26, 1997 (source 8). EMD Serono notified the agency that the products were being discontinued in letters dated July 11, 2008 and December 2, 2008.

After a citizen petition dated October 12, 2012, the agency published a determination on March 4, 2013 that the Geref products “were not withdrawn from sale for reasons of safety or effectiveness” (source 8). The notice explained that this finding allows the agency to approve abbreviated new drug applications that refer to those listed products, provided all other legal and regulatory requirements are met. It was a procedural determination about why the listed products left the market, not a new review of the compound.

The clinical literature from the Geref period was summarized in the 1999 Prakash and Goa review (source 7). Among its points, the review described intravenous sermorelin as having been used as a provocative test of pituitary growth hormone secretion, and noted that a normal response to that test could not exclude a deficit of hypothalamic origin (source 7).

What remains unresolved in the sermorelin literature?

The foundational chemistry is old and narrow. The potency figures that define sermorelin come from a single 1984 in vitro assay in rat pituitary cells (source 3), and potency ratios measured in one cell system do not establish how the fragment behaves in other models. The 1989 degradation data for GHRH(1-29)-NH2 come from plasma incubations, while the in vivo evidence in that paper concerned the full-length hormone in transgenic pig plasma (source 5).

The regulatory record is equally specific. The 2013 notice addressed the reason for a 2008 discontinuation (source 8); it did not evaluate material produced outside those approved applications. Much of the clinical work on the compound predates current analytical methods and was gathered in a review published in 1999 (source 7).

For laboratories, the practical point is structural. Sermorelin, native GHRH and modified GRF(1-29) analogs differ by defined lengths and substitutions, so confirming the expected molecular weight by mass spectrometry and checking purity by HPLC are the routine ways to tell them apart. Another GHRH analog, tesamorelin, is described on its research page.